Recent experiments in our laboratory indicate that two serogroups of tick transmitted viruses, Dhori (DHO) and Thogoto (THO), share a remarkable number of molecular features with established members of the Orthomyxoviridae. These enveloped, single-stranded RNA viruses contain seven genome segments. The 3' terminal sequences are homologous with the 3' terminal sequences of influenza A, B, and C viruses, suggesting a common evolutionary progenitor. While these viruses share a similar molecular biology with the orthomyxoviruses, the adaptation of DHO and THO viruses to a mode of transmission involving an arthropod vector is a unique pathogenetic feature. We propose to examine four areas concerning the molecular biology of these viruses: 1) to determine whether DHO viruses will reassort among related strains and, if so, to use the reassortants to determine gene segment coding assignments; 2) to isolate host range mutants of DHO virus which replicate in vertebrate but not invertebrate cells for the purpose of defining the gene(s) required for invertebrate cell growth; 3) to study the virion structure by isolating viral nucleocapsids and by protease treatment of virus particles to determine the location of virion polypeptides; and 4) to sequence cDNA clones derived from the two small RNA segments (6 and 7) of prototype DHO virus (I-611313). Sequence data from these DHO RNA segments will be examined for possible homology with influenza virus sequences. The discovery of viruses possessing molecular properties similar to those of influenza viruses yet possessing a dramatically altered pathogenesis and epidemiology provides the unusual opportunity to determine the molecular basis for these adaptations. We feel that these studies will contribute to an understanding of the unique molecular and biologic adaptations which allow the growth of these viruses in arthropod cells.